Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of psoriasis. Although the therapy of psoriasis remains elusive, targeting treatment to reduce oxidative stress is considered a potential option. Our study demonstrates the anti-inflammatory effects of a natural furocoumarin, imperatorin, on activated human neutrophils and psoriasiform dermatitis in mice.
Results:
Imperatorin inhibited superoxide anion generation, neutrophil adhesion, and migration in N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-stimulated human neutrophils. Further studies showed that imperatorin induced a decrease in cAMP-specific phosphodiesterase (PDE) activity, and increased intracellular cAMP levels and protein kinase A (PKA) activity in human neutrophils. The enzyme activities of PDE4 subtypes, but not PDE3 and PDE7, were inhibited by imperatorin. Furthermore, imperatorin inhibited the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), as well as Ca2+ mobilization in fMLF-stimulated neutrophils. These suppressive effects of imperatorin on cell responses and signaling were reversed by PKA inhibitor, suggesting that cAMP/PKA is involved in the anti-inflammatory effects of imperatorin. In vivo studies of imiquimod- and interleukin-23-induced mouse psoriasiform dermatitis demonstrated that imperatorin alleviated skin desquamation, epidermal thickening, keratinocyte hyperproliferation, and neutrophil infiltration.
Innovation and Conclusion:
Our results demonstrate that imperatorin inhibits human neutrophil respiratory burst, adhesion, and migration through the elevation of cAMP/PKA to inhibit Akt, ERK, JNK, and Ca2+ mobilization. Imperatorin is a natural inhibitor of PDE4A/B/C and may serve as a lead for developing new therapeutics to treat neutrophilic psoriasis. Antioxid. Redox Signal. 35, 885–903.
Get full access to this article
View all access options for this article.
References
1.
AbadMJ, de las HerasB, SilvanAM, PascualR, BermejoP, RodriquezB, and VillarAM. Effects of furocoumarins from Cachrys trifida on some macrophage functions. J Pharm Pharmacol, 53: 1163–1168, 2001.
2.
BabiorBM, KipnesRS, and CurnutteJT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest, 52: 741–744, 1973.
3.
Bengis-GarberC and GruenerN. Protein kinase A downregulates the phosphorylation of p47 phox in human neutrophils: a possible pathway for inhibition of the respiratory burst. Cell Signal, 8: 291–296, 1996.
4.
BoehnckeWH and SchonMP. Psoriasis. Lancet, 386: 983–994, 2015.
5.
BrechardS and TschirhartEJ. Regulation of superoxide production in neutrophils: role of calcium influx. J Leukoc Biol, 84: 1223–1237, 2008.
6.
CaoYJ, HeX, WangN, and HeLC. Effects of imperatorin, the active component from Radix Angelicae (Baizhi), on the blood pressure and oxidative stress in 2K, 1C hypertensive rats. Phytomedicine, 20: 1048–1054, 2013.
7.
CarboneA, MontalbanoA, SpanoV, MusanteI, GaliettaLJV, and BarrajaP. Furocoumarins as multi-target agents in the treatment of cystic fibrosis. Eur J Med Chem, 180: 283–290, 2019.
8.
CassatellaMA, GasperiniS, and RussoMP. Cytokine expression and release by neutrophils. Ann N Y Acad Sci, 832: 233–242, 1997.
9.
ChoochuayK, ChunhachaP, PongrakhananonV, LuechapudipornR, and ChanvorachoteP. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. J Nat Med, 67: 599–606, 2013.
10.
ChouSY, HsuCS, WangKT, WangMC, and WangCC. Antitumor effects of osthol from Cnidium monnieri: an in vitro and in vivo study. Phytother Res, 21: 226–230, 2007.
11.
ColemanRA, SmithWL, and NarumiyaS. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev, 46: 205–229, 1994.
12.
Diaz-PerezJA, KilleenME, YangY, CareyCD, FaloLDJr., and MathersAR. Extracellular ATP and IL-23 form a local inflammatory circuit leading to the development of a neutrophil-dependent psoriasiform dermatitis. J Invest Dermatol, 138: 2595–2605, 2018.
13.
EgebergA, ThyssenJP, WuJJ, and SkovL. Risk of first-time and recurrent depression in patients with psoriasis: a population-based cohort study. Br J Dermatol, 180: 116–121, 2019.
14.
Fan ChungK. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol, 533: 110–117, 2006.
15.
Glennon-AltyL, HackettAP, ChapmanEA, and WrightHL. Neutrophils and redox stress in the pathogenesis of autoimmune disease. Free Radic Biol Med, 125: 25–35, 2018.
16.
GudjonssonJE, JohnstonA, DysonM, ValdimarssonH, and ElderJT. Mouse models of psoriasis. J Invest Dermatol, 127: 1292–1308, 2007.
17.
GuerardS, AllaeysI, MartinG, PouliotR, and PoubellePE. Psoriatic keratinocytes prime neutrophils for an overproduction of superoxide anions. Arch Dermatol Res, 305: 879–889, 2013.
18.
GuoW, SunJ, JiangL, DuanL, HuoM, ChenN, ZhongW, WassyL, YangZ, and FengH. Imperatorin attenuates LPS-induced inflammation by suppressing NF-kappaB and MAPKs activation in RAW 264.7 macrophages. Inflammation, 35: 1764–1772, 2012.
19.
HanG, HavnaerA, LeeHH, CarmichaelDJ, and MartinezLR. Biological depletion of neutrophils attenuates pro-inflammatory markers and the development of the psoriatic phenotype in a murine model of psoriasis. Clin Immunol, 210: 108294, 2020.
20.
HuangGJ, DengJS, LiaoJC, HouWC, WangSY, SungPJ, and KuoYH. Inducible nitric oxide synthase and cyclooxygenase-2 participate in anti-inflammatory activity of imperatorin from Glehnia littoralis. J Agric Food Chem, 60: 1673–1681, 2012.
21.
HwangTL, SuYC, ChangHL, LeuYL, ChungPJ, KuoLM, and ChangYJ. Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils. J Lipid Res, 50: 1395–1408, 2009.
22.
IghaniA, GeorgakopoulosJR, ShearNH, WalshS, and YeungJ. Long-term 52-week trends in apremilast safety outcomes for treatment of psoriasis in clinical practice: a multicentre, retrospective case series. Br J Dermatol, 180: 211–212, 2019.
23.
IveyFD, WangL, DemirbasD, AllainC, and HoffmanCS. Development of a fission yeast-based high-throughput screen to identify chemical regulators of cAMP phosphodiesterases. J Biomol Screen, 13: 62–71, 2008.
24.
KyoiT, NodaK, OkaM, and UkaiY. Irsogladine, an anti-ulcer drug, suppresses superoxide production by inhibiting phosphodiesterase type 4 in human neutrophils. Life Sci, 76: 71–83, 2004.
25.
LaiR, XianD, XiongX, YangL, SongJ, and ZhongJ. Proanthocyanidins: novel treatment for psoriasis that reduces oxidative stress and modulates Th17 and Treg cells. Redox Rep, 23: 130–135, 2018.
26.
LamontagneS, MeadowsE, LukP, NormandinD, MuiseE, BouletL, PonDJ, RobichaudA, RobertsonGS, MettersKM, and NantelF. Localization of phosphodiesterase-4 isoforms in the medulla and nodose ganglion of the squirrel monkey. Brain Res, 920: 84–96, 2001.
27.
LeuYL, ChenYW, YangCY, HuangCF, LinGH, TsaiKS, YangRS, and LiuSH. Extract isolated from Angelica hirsutiflora with insulin secretagogue activity. J Ethnopharmacol, 123: 208–212, 2009.
28.
LiX, ZengX, SunJ, LiH, WuP, FungKP, and LiuF. Imperatorin induces Mcl-1 degradation to cooperatively trigger Bax translocation and Bak activation to suppress drug-resistant human hepatoma. Cancer Lett, 348: 146–155, 2014.
29.
LinYK, YangSH, ChenCC, KaoHC, and FangJY. Using imiquimod-induced psoriasis-like skin as a model to measure the skin penetration of anti-psoriatic drugs. PLoS One, 10: e0137890, 2015.
30.
MarquezN, SanchoR, BalleroM, BremnerP, AppendinoG, FiebichBL, HeinrichM, and MunozE. Imperatorin inhibits T-cell proliferation by targeting the transcription factor NFAT. Planta Med, 70: 1016–1021, 2004.
31.
MauriceDH, KeH, AhmadF, WangY, ChungJ, and ManganielloVC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov, 13: 290–314, 2014.
32.
MiroX, Perez-TorresS, PuigdomenechP, PalaciosJM, and MengodG. Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. Synapse, 45: 259–269, 2002.
33.
MittalM, SiddiquiMR, TranK, ReddySP, and MalikAB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal, 20: 1126–1167, 2014.
34.
NakagomeK, MatsushitaS, and NagataM. Neutrophilic inflammation in severe asthma. Int Arch Allergy Immunol 158(Suppl, 1): 96–102, 2012.
35.
OhHA, KimHM, and JeongHJ. Distinct effects of imperatorin on allergic rhinitis: imperatorin inhibits caspase-1 activity in vivo and in vitro. J Pharmacol Exp Ther, 339: 72–81, 2011.
36.
PopovI and LewinG. A deficient function of the antioxidative system of the organism as an aetiopathogenetic factor in psoriasis. Med Hypotheses, 35: 229–236, 1991.
37.
PuigL, KirbyB, MallbrisL, and StrohalR. Psoriasis beyond the skin: a review of the literature on cardiometabolic and psychological co-morbidities of psoriasis. Eur J Dermatol, 24: 305–311, 2014.
38.
RafaelA and TorresT. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors. Eur J Dermatol, 26: 3–8, 2016.
39.
Rocha-PereiraP, Santos-SilvaA, RebeloI, FigueiredoA, QuintanilhaA, and TeixeiraF. Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease. Clin Chim Acta, 303: 33–39, 2001.
40.
SchonMP, BroekaertSM, and ErpenbeckL. Sexy again: the renaissance of neutrophils in psoriasis. Exp Dermatol, 26: 305–311, 2017.
41.
SenBB, RifaiogluEN, EkizO, InanMU, SenT, and SenN. Neutrophil to lymphocyte ratio as a measure of systemic inflammation in psoriasis. Cutan Ocul Toxicol, 33: 223–227, 2014.
42.
SinghTP, SchonMP, WallbrechtK, MichaelisK, RinnerB, MayerG, SchmidbauerU, StrohmaierH, WangXJ, and WolfP. 8-Methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder. J Immunol, 184: 7257–7267, 2010.
43.
SkovL, ThomsenSF, KristensenLE, DodgeR, HedegaardMS, and KjellbergJ. Cause-specific mortality in patients with psoriasis and psoriatic arthritis. Br J Dermatol, 180: 100–107, 2019.
44.
SteffenS, AbrahamS, HerbigM, SchmidtF, BlauK, MeisterfeldS, BeissertS, GuckJ, and GuntherC. Toll-like receptor-mediated upregulation of CXCL16 in psoriasis orchestrates neutrophil activation. J Invest Dermatol, 138: 344–354, 2018.
45.
SumidaH, YanagidaK, KitaY, AbeJ, MatsushimaK, NakamuraM, IshiiS, SatoS, and ShimizuT. Interplay between CXCR2 and BLT1 facilitates neutrophil infiltration and resultant keratinocyte activation in a murine model of imiquimod-induced psoriasis. J Immunol, 192: 4361–4369, 2014.
46.
SunJ, ChiG, SoromouLW, ChenN, GuanM, WuQ, WangD, and LiH. Preventive effect of imperatorin on acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol, 14: 369–374, 2012.
47.
SwindellWR, MichaelsKA, SutterAJ, DiaconuD, FritzY, XingX, SarkarMK, LiangY, TsoiA, GudjonssonJE, and WardNL. Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis. Genome Med, 9: 24, 2017.
48.
TakeyaR and SumimotoH. Regulation of novel superoxide-producing NAD(P)H oxidases. Antioxid Redox Signal, 8: 1523–1532, 2006.
49.
TanAS and BerridgeMV. Superoxide produced by activated neutrophils efficiently reduces the tetrazolium salt, WST-1 to produce a soluble formazan: a simple colorimetric assay for measuring respiratory burst activation and for screening anti-inflammatory agents. J Immunol Methods, 238: 59–68, 2000.
50.
TorphyTJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med, 157: 351–370, 1998.
51.
TsaiYF, ChenCY, ChangWY, SyuYT, and HwangTL. Resveratrol suppresses neutrophil activation via inhibition of Src family kinases to attenuate lung injury. Free Radic Biol Med, 145: 67–77, 2019.
52.
TsaiYF, ChuTC, ChangWY, WuYC, ChangFR, YangSC, WuTY, HsuYM, ChenCY, ChangSH, and HwangTL. 6-Hydroxy-5,7-dimethoxy-flavone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury. Free Radic Biol Med, 106: 379–392, 2017.
53.
TsaiYF, YangSC, and HwangTL. Formyl peptide receptor modulators: a patent review and potential applications for inflammatory diseases (2012–2015). Expert Opin Ther Pat, 26: 1139–1156, 2016.
54.
TsaiYF, YuHP, ChungPJ, LeuYL, KuoLM, ChenCY, and HwangTL. Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4. Free Radic Biol Med, 89: 387–400, 2015.
55.
VallatVP, GilleaudeauP, BattatL, WolfeJ, NabeyaR, HeftlerN, HodakE, GottliebAB, and KruegerJG. PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J Exp Med, 180: 283–296, 1994.
56.
van der FitsL, MouritsS, VoermanJS, KantM, BoonL, LamanJD, CornelissenF, MusAM, FlorenciaE, PrensEP, and LubbertsE. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol, 182: 5836–5845, 2009.
57.
WellsJM, JacksonPL, VieraL, BhattSP, GautneyJ, HandleyG, KingRW, XuX, GaggarA, BaileyWC, DransfieldMT, and BlalockJE. A randomized, placebo-controlled trial of roflumilast. Effect on proline-glycine-proline and neutrophilic inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 192: 934–942, 2015.
58.
WinterbournCC, KettleAJ, and HamptonMB. Reactive oxygen species and neutrophil function. Annu Rev Biochem, 85: 765–792, 2016.
59.
YuHP, HsiehPW, ChangYJ, ChungPJ, KuoLM, and HwangTL. DSM-RX78, a new phosphodiesterase inhibitor, suppresses superoxide anion production in activated human neutrophils and attenuates hemorrhagic shock-induced lung injury in rats. Biochem Pharmacol, 78: 983–992, 2009.
60.
ZemansRL and MatthayMA. What drives neutrophils to the alveoli in ARDS?. Thorax, 72: 1–3, 2017.
61.
ZhangX, LiW, AbudurehemanA, ChengT, and PengP. Imperatorin possesses notable antiinflammatory activity in vitro and in vivo through inhibition of the NFkappaB pathway. Mol Med Rep, 16: 8619–8626, 2017.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
